Luteinizing hormone-releasing hormone is the decapeptide pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH.sub.2 (LHRH). It binds to specific membrane-bound receptors on the gonadotropes and stimulates them to secrete luteinizing hormone (LH) and follicle-stimulating hormone (FSH). (R. N. Clayton and K. J. Catt, Endocr Rev (1981) 2: 186.)
Peptides are compounds which contain two or more amino acids in which the carboxyl group of one acid is linked to the amino group of the other acid as an amide. The formula for LHRH, as represented above, is in accordance with conventional representations of peptides where the amino terminus appears to the left and the carboxyl terminus to the right. The position of the various amino acid residues is indicated by numbering from left to right. In the case of LHRH, the hydroxyl portion of the carboxylic acid of the 10-position amino acid has been replaced with an amino group to give an amide function.
Over fifteen hundred agonist and antagonist analogs of LHRH in which one or more of the peptide amino acid residues are replaced or modified have been synthesized. An excellent review of much of the work is given in the book LHRH and Its Analogs, Contraceptive and Therapeutic Applications, B. H. Vickery et al, eds, MTP Press Limited, Lancaster, PA, 1984 ("Vickery et al").
As set out by J. J. Nestor, Jr. in chapter 1 of that book, a range of agonist analogs of LHRH have been prepared, including nonapeptide alkyl amides such as [Pro.sup.9 -NHEt] LHRH and buserelin ([D-Ser(t-Bu).sup.6, Pro.sup.9 -NHEt] LHRH) and material incorporating an Aza-Gly(NHNHCO-) in position 10. In addition, modification in position 6, especially by adding hydrophobic groups, has been shown to enhance activity. LHRH and its agonist analogs have been proposed for use in male and female contraception, treatment of precocious puberty, endometriosis, first trimester pregnancy interruption, and the treatment of breast and prostate tumors.
As pointed out by M. V. Nekola et al in chapter 10 of the Vickery et al text, LHRH antagonists have been synthesized having substitution in one or more of the 1, 2, 3, 6, and 10 positions. Such materials can be used to prevent the release of the LH and FSH gonadotropins so as to inhibit ovulation and terminate pregnancy and to produce a male contraceptive effect by interrupting spermatogenesis. These antagonists are useful as well in treating breast, prostate, and other reproductive tissue cancers, nonreproductive organ tumors, and ectopic tumors, particularly those secreting chorionic gonadotropin. Other uses for LHRH antagonist analogs include treatment of endometriosis and the symptoms of menopause.
The art surrounding LHRH, its analogs, and their activities is substantial. In addition to the collection of papers on the subject in Vickery et al, representative articles and patents include: U.S. Pat. No. 4,444,759 of Rivier et al, which discloses LHRH analogs modified at the 1, 2, 5, 6, and/or 7 positions and carrying a Gly--NH.sub.2, NH--CH.sub.2 --CH.sub.3 or D--Ala--NH.sub.2 at the 10 position; U.S. Pat. No. 4,341,767 of Nestor et al, which shows LHRH antagonists having the LHRH structure substituted at the 1, 2, 3 and/or 6 positions with a glycinamide or a --HN--R' (wherein R' is an alkyl or the like) at the 10 position; U.S. Pat. No. 4,410,514 of Vale et al showing a decapeptide similar to LHRH which promotes fish spawning and which has variable amino acid residues at its 6 and 10 positions; U.S. Pat. No. 4,431,635 of Coy et al, which shows LHRH antagonists having variable amino acid residues at the 1, 2, and 6 positions and optionally at the 3 and 10 positions; Biochem Biophys Res Comm (1979) 86, 4: 1266 by Channabasavaiah et al, which discloses 1, 2, 3, 6-modified analogs of LHRH and their ability to inhibit ovulation in rodents; J Med Chem (1974) 17, 9: 1016, by Rees et al, which shows a variety of 2-modified analogs of LHRH and their agonist and antagonist activity; J Med Chem (1975) 18, 12: 1247, of Beattie et al, which shows a group of 2, 6-modified analogs; and Ann Clin Res (1978) 10: 139, of Coy and Schally, which shows that LHRH analogs wherein the position 10 glycine-amide residue is replaced with an alkyl amide are active in LH release.
Two other references that are co-authored by the present inventor are Tetrahedron Letters (1982) 23, 25: 2533-2534, which concerns synthesis of ketomethylene analogs of dipeptides; and J Med Chem (1980) 23: 1392, which is related to a ketomethylene analog of a tripeptide inhibitor of angiotensin. Neither of these last two references discloses LHRH analogs or discusses their activity.
Other references which mention ketomethylene substitution of peptides are U.S. Pat. No. Re. 30,731, of Hudson et al, reissued on Sep. 1, 1981, British Pat. No. 1,587,809, and German O.L.S. No. 2811267 of National Research Development Corporation, London, and PCT W084/03507 of Ferring A.B.
One drawback to the use of LHRH and its agonist and antagonist analogs has been their low activity following oral administration. Oral doses are often as much as 1,000 times or 10,000 times less active than the parenteral (subcutaneous injection) dose. Oral doses are often much less active (such as 100 times less active) than nasally administered material. By the present invention, a structural modification in the chain of LHRH and its analogs is provided which substantially increases their oral activity.